The majority of patients having formed kidney stones composed of calcium oxalate and/or apatite demonstrate hypercalciuria when compared to normal subjects without a personal or family history of stones. Stone formers exhibit hypercalciuria at all levels of dietary Ca intakes as well as increased urinary and salivary Ca when fasting suggesting a cellular Ca leak. The resulting elevations of urinary Ca concentrations appear to be an important determinant of Ca-salt crystalluria and stone growth. In addition, Ca-stone formers demonstrate hypophosphatemia, augmented fractional renal PO4 excretion, and elevations of fasting salivary PO4 concentrations. On the average, serum immunoreactive parathyroid hormone concentrations are normal among Ca-stone formers but in recent observations we have shown that plasma, 1,25-(OH)2-D concentrations are elevated in comparision to normal subjects. These high plasma 1,25-(OH)2-D levels are inversely related to serum PO4 concentrations. Furthermore, dietary PO4 deprivation in healthy women, but not men, results in a fall in serum PO4 and a reciprocal rise in plasma, 1,25-(OH)2-D concentrations. Since PO4 deprivation in animals, regardless of parathyroid function, activates renal 1,25-(OH)2-D synthesis, these observations suggest that a primary abnormality in PO4 homeostasis leading to activation of the renal 25-OH-D-1 alpha-hydroxylase may be a fundamental abnormality underlying Ca-stone disease. We propose to continue studies designed to clarify the mechanisms responsible for the three-fold variation in serum, 1,25-(OH)2-D concentrations in healthy populations as well as the mechanisms by which serum 1,25-(OH)2-D concentrations are elevated among patients having recurrent calcium containing kidney stones. We will evaluate plasma levels and the turnover in metabolism in injected 3H,1,25-(OH)2-D3 in response to normal and low calcium diets as well as normal and low phosphorus diets. We will also examine the response to changes in dietary magnesium and to the administration of thiazide diuretics. We will attempt to devise a method to search for differences in in vitro phosphate transport between normal subjects and calcium stone formers. We will re-evaluate the classification of calcium stone disease.